Excess adiposity is a risk factor for postmenopausal breast cancer and a major risk factor for recurrence in both pre- and postmenopausal breast cancer, and the biological mechanisms are not fully understood. Obesity is associated with elevated endogenous circulating estrogen as well as activation of the immune system, a key causative factor in insulin resistance and hyperinsulinemia. Optimal macronutrient distribution of weight loss diets has not been established. Cancer control guidelines have historically encouraged a lowfat diet, but current evidence does not suggest this strategy to be of particular benefit. Emerging evidence suggests that the optimal diet composition for weight loss may differ across individuals based on metabolic status and genetic factors. Effects of diet composition on hormonal and other factors linking obesity to breast cancer in weight loss interventions have not been compared or examined. The specific aims ofthis study are: (1) To examine whether there is a differential weight loss response to different dietary macronutrient composition in a weight loss intervention in healthy obese women, depending on insulin resistance status; (2). To examine whether there is a differential response (depending on insulin resistance status) to different dietary macronutrient composition in a weight loss intervention in the hormonal factors and markers of inflammation that may link obesity to breast cancer mortality (insulin, SHBG, estrogens, C-reactive protein, interleukin-6 [IL-6], tumor necrosis factor a [TNF-a], and as a marker for gene expression, IL-6 and TNF-a gene methylation); and (3) To identify nutrient-gene interactions that contribute to differential response of cytokines to weight loss and diet composition associated with polymorphisms in IL-6 and TNF-a genes. These aims will be addressed in a randomized controlled study involving 156 obese women randomly assigned to a high-carbohydrate (65% energy) low-fat (20% energy) or low-carbohydrate (45% energy) highmonounsaturated fat (35% energy) diet in a 12-month behavioral weight loss program. We hypothesize that greater weight loss and reduction in biomarkers will occur in insulin resistant women assigned to the lower carbohydrate, higher fat diet. We also hypothesize that the ability of weight loss and diet modification to decrease IL-6 and TNF-a concentrations will be influenced by polymorphisms in these genes. Results of this study will help to refine and individualize dietary guidance for optimal weight control and breast cancer prevention and will contribute to knowledge of mechanisms that link insulin resistance, inflammation and obesity to risk and progression of breast cancer.